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WO2005046674A2 - Compositions antibacteriennes - Google Patents

Compositions antibacteriennes Download PDF

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Publication number
WO2005046674A2
WO2005046674A2 PCT/GB2004/004624 GB2004004624W WO2005046674A2 WO 2005046674 A2 WO2005046674 A2 WO 2005046674A2 GB 2004004624 W GB2004004624 W GB 2004004624W WO 2005046674 A2 WO2005046674 A2 WO 2005046674A2
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WO
WIPO (PCT)
Prior art keywords
compound
dehydro
amino
alkoxy
aminopyrrolizidine
Prior art date
Application number
PCT/GB2004/004624
Other languages
English (en)
Other versions
WO2005046674A3 (fr
Inventor
Robert James Nash
Paul Wolferstan
George William John Fleet
Jeroen Van Ameijde
Graeme Horne
Original Assignee
M N L Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by M N L Pharma Limited filed Critical M N L Pharma Limited
Publication of WO2005046674A2 publication Critical patent/WO2005046674A2/fr
Publication of WO2005046674A3 publication Critical patent/WO2005046674A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents

Definitions

  • the present invention relates to (alkyl)a inopyrrolizidine compounds and to their use in medicine.
  • the invention relates to the use of (alkyl)aminopyrrolizidine compounds as antibacterial drugs.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • Anthrax is caused by the bacterium Bacillus anthracis. While anthrax commonly affects hoofed animals such as sheep and goats, humans may also acquire this disease. Historically, the principal risk factor for inhalation anthrax is the inhalation of anthrax spores from industrial processes such hide tanning and wool processing. However, anthrax has recently been used as a biological weapon in bio-terrorism.
  • the first stage can last from hours to a few days and is similar to a flu-like illness with fever, headache, cough, shortness of breath, and chest pain.
  • the second stage often develops suddenly and is characterized by shortness of breath, fever, and shock.
  • the prognosis of inhalation anthrax once it reaches the second stage is poor, even with antibiotic therapy and up to 90% of cases in the second stage are fatal.
  • an antibacterial (alkyl)aminopyrrolizidine compound which compound is: (a) for use in therapy or prophylaxis, and/or (b) in a pharmaceutical composition, and/or (c) in a unit dosage form, and/or (d) in a form suitable for local or systemic administration.
  • the compound may be a pharmaceutically acceptable derivative of loline:
  • Loline is a naturally-occurring alkaloid found, for example, in certain grasses.
  • the compound has a saturated or unsaturated (alkyl)aminopyrrolizidine nucleus of formula:
  • the compound may have a saturated or unsaturated (alkyl)aminopyrrolizidine nucleus of formula:
  • the compounds are hydroxylated. Particularly preferred are compounds which are mono- or dihydroxylated.
  • R 1 is amino or alkyl amino
  • R 2 and R 3 are independently selected from hydrogen, oxo, halo, hydroxy and alkoxy and wherein the compound is:
  • the alkyl amino is preferably C1-C10 alkyl amino (for example, Ci-Ce alkyl amino, e.g. C1-C4 alkyl amino).
  • the alkoxy is preferably C1-C10 alkoxy (for example, Ci-C ⁇ alkoxy, e.g. C ⁇ Cn alkoxy).
  • the alkyl amino may be a Ci, C2, C3, C4, C5 or C ⁇ alkyl amino, while the alkoxy may be a Ci, C 2 , C3, C 4 , C5 or Cs alkoxy.
  • the halo may be chloro, fluoro, iodo or bromo, preferably chloro, fluoro or iodo.
  • the compounds contemplated according to the second aspect of the invention may be saturated or unsaturated.
  • Preferred unsaturated compounds of the invention are ,2-dehydro-, 5,6-dehydro-, 6,7-dehydro or 7,8-dehydro.
  • R 2 and/or R 3 are hydroxy and/or wherein R 1 is amino or C-i alkyl amino (methylamino).
  • R 1 is Ci alkyl amino (methylamino) and R 2 and R 3 are oxo.
  • Such compounds have the formula:
  • R 1 , R 2 and R 3 are as shown below:
  • Unsaturated compounds according to the invention may also have R 1 , R 2 and R 3 as shown in the table above.
  • Such compounds may, for example, be 1 ,2-dehydro-, 5,6-dehydro-, 6,7-dehydro or 7,8-dehydro.
  • the alkoxy is preferably Ci, d, C3, C4, C 5 or C 6 alkoxy
  • the alkylamino is preferably C-i, C ⁇ , C3, C4, C 5 or C ⁇ alkylamino
  • the halo is preferably chloro, fluoro, iodo or bromo.
  • the invention provides a method of treating a bacterial infection comprising administering the compound of the invention to a patient.
  • Any bacterial infection may be treated using the compounds of the invention, but preferred are bacterial infections with a Gram-positive bacteria (especially low G+C Gram-positive bacteria, including Staphylococcus spp. or Bacillus spp.)
  • a Gram-positive bacteria especially low G+C Gram-positive bacteria, including Staphylococcus spp. or Bacillus spp.
  • the invention finds particular utility in the treatment of infection with S. aureus or S. epidermidis.
  • the compounds of the invention may also be used to treat infection with MRSA, for example selected from any of C-MSRA1 , C-MRSA2, C-MRSA3, C-MSRA4, Belgian MRSA, Swiss MRSA and any of the EMRSA strains. Accordingly, the invention therefore finds utility in the treatment or prophylaxis of infections mediated by drug- resistant bacteria and in the treatment or prophylaxis of nosocomial infections.
  • the compounds of the invention are used to treat infection with Bacillus anthracis, and the invention therefore finds utility in the treatment or prophylaxis of anthrax.
  • the invention contemplates the use of the compounds of the invention for the manufacture of a medicament for use as an antibacterial agent.
  • the invention provides a process for the manufacture of an antibacterial agent characterized in the use of the compound of the invention.
  • the invention contemplates a composition comprising the compound of the invention in combination with:
  • an antimicrobial agent e.g. antibacterial
  • an antiviral agent e.g. an antiviral agent
  • an anti-inflammatory e.g. an analgesic
  • an immunostimulant e.g. an immunostimulant.
  • compositions find particular utility in adjunctive therapies.
  • the invention also contemplates a pharmaceutical kits of parts comprising the compound of the invention, optionally in combination with an adjunctive therapeutic agent (for example those listed as (a) to (e), above).
  • Such kits may further comprise instructions for use in antibacterial treatment or prophylaxis.
  • the invention covers wound dressings, surgical implants, disinfectant scrubs, wipes and other surgical equipment or lotions comprising the compound of the invention.
  • the compound of the invention may also find application in methods for cleaning and/or sterilizing medical instruments, in pre- operative surgical scrubs and in operating theatre hygiene maintenance procedures.
  • a pharmaceutical composition is a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes.
  • the pharmaceutical compositions of the invention comprise the compound of the invention together with a pharmaceutical excipient.
  • the term isolated as applied to the compounds of the invention is used herein to indicate that the compound exists in a physical milieu distinct from that in which it occurs in nature.
  • the isolated material may be substantially isolated (for example purified) with respect to the complex cellular milieu in which it naturally occurs.
  • the absolute level of purity is not critical and those skilled in the art can readily determine appropriate levels of purity according to the use to which the material is to be put. Preferred, however, are purity levels of 90% w/w, 99% w/w or higher.
  • the isolated compound forms part of a composition (for example a more or less crude extract containing many other substances) or buffer system, which may for example contain other components.
  • the isolated compound may be purified to essential homogeneity, for example as determined spectrophotometrically, by NMR or by chromatography (for example GC-MS).
  • the pharmaceutically acceptable derivatives are therefore suitable for administration to or use in contact with the tissues of humans without undue toxicity, irritation or allergic response (i.e. commensurate with a reasonable benefit/risk ratio).
  • Preferred derivatives are those obtained (or obtainable) by alkylation, esterification or acylation of the parent pyrrolizidine compounds of the invention.
  • the derivatives may be antibacterial perse, or may be inactive until processed in vivo. In the latter case, the derivatives of the invention act as prodrugs.
  • Pharmaceutically acceptable derivatives include all prodrugs (see below). Particularly preferred prodrugs are ester derivatives which are esterified at one or more of the free hydroxyls and which are activated by hydrolysis in vivo.
  • the pharmaceutically acceptable derivatives of the invention retain some or all of the antibacterial activity of the parent compound. In some cases, the antibacterial activity is increased by derivatization. Derivatization may also augment other biological activities of the compound, for example bioavailabiiity. The term is to be understood mutatis mutandis when applied to loline.
  • prodrug is intended to define any covalently bonded carriers which release the antibacterial compounds of the invention in vivo when the prodrug is administered.
  • Prodrugs may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation ex vivo prior to administration or in vivo, to the antibacterial compound of the invention.
  • Prodrugs therefore include compounds of the invention wherein a hydroxy or amino group is bonded to any group that, when the prodrug is administered, cleaves to form a free hydroxyl or free amino group, respectively.
  • examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention.
  • pharmaceutically acceptable salt as applied to the compounds of the invention defines any non-toxic organic or inorganic acid addition salt of the free base compounds which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and which are commensurate with a reasonable benefit risk ratio. Suitable pharmaceutically acceptable salts are well known in the art.
  • Examples are the salts with inorganic acids (for example hydrochloric, hydrobromic, sulphuric and phosphoric acids), organic carboxylic acids (for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 2-phenoxybenzoic, 2- acetoxybenzoic and mandelic acid) and organic sulfonic acids (for example methanesulfonic acid and p- toluenesulfonic acid).
  • organic carboxylic acids for example acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic
  • the drugs of the invention may also be converted into salts by reaction with an alkali metal halide, for example sodium chloride, sodium iodide or lithium iodide.
  • an alkali metal halide for example sodium chloride, sodium iodide or lithium iodide.
  • the compounds of the invention are converted into their salts by reaction with a stoichiometric amount of sodium chloride in the presence of a solvent such as acetone.
  • salts and the free base compounds can exist in either a hydrated or a substantially anhydrous form.
  • Crystalline forms of the compounds of the invention are also contemplated and in general the acid addition salts of the compounds of the invention are crystalline materials which are soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, demonstrate higher melting points and an increased solubility.
  • the present invention contemplates all optical isomers, racemic forms and diastereomers of the compounds of the invention.
  • the compounds of the invention may exist and be synthesised and/or isolated in optically active and racemic forms.
  • references to the compounds of the present invention encompass the compounds as a mixture of diastereomers, as individual diastereomers, as a mixture of enantiomers as well as in the form of individual enantiomers. Therefore, the present invention contemplates all optical isomers and racemic forms thereof of the compounds of the invention, and unless indicated otherwise (e.g.
  • the compounds shown herein are intended to encompass all possible optical isomers of the compounds so depicted.
  • the invention contemplates use of an isolated eutomer.
  • antibacterial is used hereinto define a compound that is capable of destroying bacteria or inhibiting or preventing bacterial growth or metabolism.
  • Those skilled in the art will be aware of many different tests for detecting and/or quantifying antibacterial activity, including for example cup plate or paper disc bioassays based on the detection/measurement of zones of inhibition in seeded agar plates.
  • adjunctive as applied to the use of the compounds of the invention in therapy
  • Such adjunctive therapies may comprise the concurrent, separate or sequential administration/application of the compound of the invention and the other treatment(s).
  • adjunctive use of the compound of the invention is reflected in the formulation of the pharmaceutical compositions of the invention.
  • adjunctive use may be reflected in a specific unit dosage, or in formulations in which the compound of the invention is present in admixture with the other drug(s) with which it is to be used adjunctively (or else physically associated with the other drug(s) within a single unit dose).
  • adjunctive use of the compound of the invention may be reflected in the composition of the pharmaceutical kits of the invention, wherein the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the other drug(s) with which it is to be used adjunctively.
  • adjunctive use of the compound of the invention may be reflected in the content of the information and/or instructions co-packaged with the compound relating to formulation and/or posology.
  • surgical material is used herein to define all materials (including equipment, compositions, tools, clothing, dressings, containers, disposables, reagents, accessories, implants and prosthetics) used in surgical operations.
  • Gram-positive bacterium is a term of art defining a particular class of bacteria that are grouped together on the basis of certain cell wall staining characteristics.
  • low G+C Gram-positive bacterium is a term of art defining a particular subclass class of evolutionarily related bacteria within the Gram-positives on the basis of the composition of the bases in the DNA.
  • the subclass includes Streptococcus spp., Staphylococcus spp., Listeria spp., Bacillus spp., Clostridium spp. and Lactobacillus spp.).
  • the invention finds application in medicine, for example in methods of therapy and prophylaxis.
  • the medical applications may be applied to any warm-blooded animal, including humans.
  • the applications include veterinary applications, wherein the compounds of the invention are administered to non-human animals, including primates, dogs, cats, horses, cattle and sheep.
  • the compounds of the invention are antibacterial agents.
  • the compounds of the invention find general application as antibacterial agents. They may therefore be used in the treatment or prophylaxis or diagnosis of any bacterial infection.
  • the compounds of the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • oral or parenteral routes including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
  • the amount of the compound administered can vary widely according to the particular dosage unit employed, the period of treatment, the age and sex of the patient treated, the nature and extent of the disorder treated, and the particular compound selected.
  • the compounds of the invention can be used in conjunction with other agents known to be useful in the treatment of bacterial diseases, disorders or infections and in such embodiments the dose may be adjusted accordingly.
  • the effective amount of the compound administered will generally range from about 0.01 mg/kg to 500 mg/kg daily.
  • a unit dosage may contain from 0.05 to 500 mg of the compound, and can be taken one or more times per day.
  • the compound can be administered with a pharmaceutical carrier using conventional dosage unit forms either orally, parenterally, or topically, as described below.
  • a suitable dose will be in the range of 0.01 to 500 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 50 mg per kilogram body weight per day and most preferably in the range 1 to 5 mg per kilogram body weight per day.
  • the desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day.
  • These sub-doses may be administered in unit dosage forms, for example, containing 0.001 to 100 mg, preferably 0.01 to 10 mg, and most preferably 0.5 to 1.0 mg of active ingredient per unit dosage form.
  • compositions of the invention comprise the compound of the invention, optionally together with a pharmaceutically acceptable excipient.
  • the compound of the invention may take any form. It may be synthetic, purified or isolated from natural sources. When purified from a natural source, the compound of the invention may be isolated or merely purified.
  • any suitable excipient may be used, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • compositions may take any suitable form, and include for example tablets, elixirs, capsules, solutions, suspensions, powders, granules and aerosols.
  • the pharmaceutical composition may take the form of a kit of parts, which kit may comprise the composition of the invention together with instructions for use and/or a plurality of different components in unit dosage form.
  • Tablets for oral use may include the compound of the invention mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
  • Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the compound of the invention is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
  • Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
  • the compounds of the invention may also be presented as liposome formulations.
  • the compound of the invention can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, granules, solutions, suspensions, dispersions or emulsions (which solutions, suspensions dispersions or emulsions may be aqueous or non-aqueous).
  • the solid unit dosage forms can be a capsule which can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and comstarch.
  • the compounds of the invention are tableted with conventional tablet bases such as lactose, sucrose, and comstarch in combination with binders such as acacia, cornstarch, or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, lubricants intended to improve the flow of tablet granulations and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example, talc, stearic acid, or magnesium, calcium, or zinc stearate, dyes, coloring agents, and flavoring agents intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
  • conventional tablet bases such as lactose, sucrose, and comstarch in combination with binders such as acacia, cornstarch, or gelatin
  • disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch
  • Suitable excipients for use in oral liquid dosage forms include diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptably surfactant, suspending agent or emulsifying agent.
  • the compounds of the invention may also be administered parenterally, that is, subcutaneously, intravenously, intramuscularly, or interperitoneally.
  • the compound is provided as injectable doses in a physiologically acceptable diluent together with a pharmaceutical carrier (which can be a sterile liquid or mixture of.liquids).
  • a pharmaceutical carrier which can be a sterile liquid or mixture of.liquids.
  • suitable liquids include water, saline, aqueous dextrose and related sugar solutions, an alcohol (such as ethanol, isopropanol, or hexadecyl alcohol), glycols (such as propylene glycol or polyethylene glycol), glycerol ketals (such as 2,2- dimethyi-1 ,3-dioxolane-4-methanol), ethers (such as poly(ethylene-glycol) 400), an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or a detergent), suspending agent (such as
  • Suitable fatty acids include oleic acid, stearic acid, and isostearic acid.
  • Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
  • Suitable soaps include fatty alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example, dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamines acetates; anionic detergents, for example, alkyl, aryl, and olefin sulphonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulphosuccinates; nonionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers; and amphoteric detergents, for example, alkyl-beta-
  • compositions of this invention will typically contain from about 0.5 to about 25% by weight of the compound of the invention in solution. Preservatives and buffers may also be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight.
  • the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
  • surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the compounds of the invention may also be administered topically, and when done so the carrier may suitably comprise a solution, ointment or gel base.
  • the base for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Topical formulations may contain a concentration of the pyrrolizidine compound or it's pharmaceutical salt from about 0.1 to about 10% w/v (weight per unit volume).
  • the compounds of the invention may be formulated for use with one or more other drug(s).
  • the compounds of the invention may be used in combination with an antimicrobial (e.g. antibacterial) agent, antiviral agent, anti-inflammatory, analgesic (e.g. opioids or NSAIDs) or immunostimulant.
  • adjunctive use may be reflected in a specific unit dosage designed to be compatible (or to synergize) with the other drug(s), or in formulations in which the compound is admixed with one or more of the antimicrobial (e.g. antibacterial) agents, antiviral agents, anti-inflammatories, analgesics or immunostimulants (or else physically associated with the other drug(s) within a single unit dose).
  • Adjunctive uses may also be reflected in the composition of the pharmaceutical kits of the invention, in which the compound of the invention is co-packaged (e.g. as part of an array of unit doses) with the antimicrobial (e.g. antibacterial) agent, antiviral agent, anti-inflammatory, analgesic or immunostimulant.
  • Adjunctive use may also be reflected in information and/or instructions relating to the co-administration of the compound with antimicrobial agents and/or antiinflammatories.
  • a semi-synthetic reaction mixture derived from loline was tested for activity by incubation for 12-24 hours at 37°C at various concentrations with a suspension of 1x10 3 c.f.u. of Bacillus anthracis SN1. After incubation, test samples were plated onto solid agar plates and colonies counted after incubation at 37°C for 24 hrs. Complete bacterial killing was observed.
  • a semi-synthetic reaction mixture derived from loline was tested for activity by incubation for 12-24 hours at 37°C at various concentrations with a suspension of 1x10 3 c.f.u. of Staphylococcus aureus. After incubation, test samples were plated onto solid agar plates and colonies counted after incubation at 37°C for 24 hrs. Complete bacterial killing was ' observed.
  • Loline hydrochloride (15 mg) was treated with DBU (2 equivalents) and TMSi (1.2 equivalents) at room temperature for 1 hour. The reaction was quenched through the addition of MeOH and the solvents were removed under reduced pressure. The crude residue was dissolved in chloroform and washed with water. Both layers were concentrated under reduced pressure aqueous and chloroform extracts of the product as shown below:

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Abstract

L'invention concerne des composés antibactériens (alkyle)aminopyrrolizidine destinés au traitement thérapeutique ou prophylactique et pouvant être des dérivés pharmaceutiquement acceptables de la loline. Des exemples de ces composés sont : 2,7-dihydroxy-1-méthylaminopyrrolizidine, 2,7-dihydroxy-1-aminopyrrolizidine, 2-hydroxy-1-aminopyrrolizidine, 2-hydroxy-1-méthylaminopyrrolizidine, 7-hydroxy-1-aminopyrrolizidine, 7-hydroxy-1-méthylaminopyrrolizidine, 1α-méthylamino-2β-hydroxypyrrolizidine, 1α-méthylamino-7β-hydroxypyrrolizidine, 1α-amino-2β-hydroxypyrrolizidine, 1α-amino-7β-hydroxypyrrolizidine, 1α-amino-2,7β-hydroxypyrrolizidine et 1α-méthylamino-2,7β-hydroxypyrrolizidine. Ces composés peuvent servir au traitement d'infections dues à un MRSA, y compris C-MSRA1, C-MRSA2, C-MRSA3, C-MSRA4, MRSA belge, MRSA suisse et une quelconque des souches EMRSA.
PCT/GB2004/004624 2003-11-04 2004-11-03 Compositions antibacteriennes WO2005046674A2 (fr)

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GB0325655.9 2003-11-04
GBGB0325655.9A GB0325655D0 (en) 2003-11-04 2003-11-04 Antibacterial compositions

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091987A1 (fr) * 2014-12-11 2016-06-16 Syngenta Participations Ag Procédés de préparation de compositions contenant un alcaloïde et utilisations de celles-ci

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5185028A (en) * 1991-08-19 1993-02-09 The United States Of America, As Represented By The Secretary Of Agriculture N-acyl loline derivatives as insecticides and herbicides
US5468486A (en) * 1992-01-21 1995-11-21 The University Of Tennessee Research Corporation Vaccine containing a protein alkaloid conjugate for the treatment of fescue toxicosis
US5372818A (en) * 1993-02-01 1994-12-13 Clemson University Method of treating fescue toxicosis with domperidone

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016091987A1 (fr) * 2014-12-11 2016-06-16 Syngenta Participations Ag Procédés de préparation de compositions contenant un alcaloïde et utilisations de celles-ci
CN106998690A (zh) * 2014-12-11 2017-08-01 先正达参股股份有限公司 制备含生物碱组合物的方法及其用途
US10820593B2 (en) 2014-12-11 2020-11-03 Syngenta Participations Ag Methods of preparing alkaloid containing compositions and uses thereof

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